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SUMMARY:Protein genetic architecture is simple\, and epistasis can facilit
 ate the evolution of new functions - Assistant Professor Brian Metzger\, P
 urdue University 
DTSTART:20241007T113000Z
DTEND:20241007T123000Z
UID:TALK216769@talks.cam.ac.uk
CONTACT:Kate Davenport
DESCRIPTION:A protein’s genetic architecture – the set of causal rules
  by which its sequence determines its function – also determines the eff
 ects of mutations and thus the possible evolutionary routes a protein may 
 take. Prior work suggests that the genetic architectures of proteins are c
 omplex\, with large amounts of high order epistasis that constrains evolut
 ion and limits the ability to predict protein function from sequence. Howe
 ver\, prior work may have overstated both the extent and impact of epistas
 is by analyzing genetic architecture from the perspective of a single refe
 rence genotype and failing to fully account for global nonlinearities – 
 both of which can artificially inflate estimates of epistasis – and by c
 onsidering only a single protein function and direct evolutionary paths be
 tween pairs of proteins – both of which make epistasis a constraint on e
 volution. Here I will describe a reference-free method for inferring prote
 in genetic architecture from combinatorial deep mutational scanning datase
 ts that accounts for global nonlinearities. Applying this approach to 20 p
 reviously collected datasets reveals that the genetic architecture of most
  proteins studied to date are simple: main and pairwise interactions among
  amino acids\, along with a simple nonlinear correction\, explains a media
 n of 96% of phenotypic variance (>92% in every case). We further used this
  approach to dissect the genetic architecture and evolution of a transcrip
 tion factor’s specificity for DNA by combining deep mutational scanning 
 with ancestral protein reconstruction. As before\, the genetic architectur
 e was simple\, with few high order interactions and many main and pairwise
  interactions instead. However\, these pairwise interactions massively exp
 anded the number of opportunities for single-residue mutations to switch s
 pecificity from one DNA element to another. By bringing variants with diff
 erent specificities close together in sequence space\, pairwise epistatic 
 interactions can thus facilitate the evolution of new molecular functions.
  By reorienting how we estimate epistasis\, reference-free analyses can re
 veal simple and intelligible protein genetic architectures and thus provid
 e an experimentally and analytically tractable route forward for understan
 ding protein genetic architecture and its evolution. 
LOCATION:CRUK CI Lecture Theatre
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